Chronic Kidney Injury Research Articles

Inhibition of RIPK1 or RIPK3 kinase activity post ischemia-reperfusion reduces the development of chronic kidney injury.

Ischemia-reperfusion injury (IRI) occurs when the blood supply to an organ is temporarily reduced and then restored. Kidney IRI is a form of acute kidney injury (AKI), which often progresses to kidney fibrosis. Necroptosis is a regulated necrosis pathway that has been implicated in kidney IRI. Necroptotic cell death involves the recruitment of the RIPK1 and RIPK3 kinases and the activation of the terminal effector, the mixed lineage kinase domain-like (MLKL) pseudokinase. Phosphorylated MLKL causes cell death by plasma membrane rupture, driving 'necroinflammation'. Owing to their apical role in the pathway, RIPK1 and RIPK3 have been implicated in the development of kidney fibrosis. Here, we used a mouse model of unilateral kidney IRI to assess whether the inhibition of RIPK1 or RIPK3 kinase activity reduces AKI and the progression to kidney fibrosis. Mice treated with the RIPK1 inhibitor Nec-1s, either before or after IR, showed reduced kidney injury at 24 hr compared with controls, whereas no protection was offered by the RIPK3 inhibitor GSK´872. In contrast, treatment with either inhibitor from days 3 to 9 post-IR reduced the degree of kidney fibrosis at day 28. These findings further support the role of necroptosis in IRI and provide important validation for the contribution of both RIPK1 and RIPK3 catalytic activities in the progression of kidney fibrosis. Targeting the necroptosis pathway could be a promising therapeutic strategy to mitigate kidney disease following IR.

Trehalose activates autophagy to alleviate cisplatin-induced chronic kidney injury by targeting the mTOR-dependent TFEB signaling pathway

Trehalose activates autophagy to alleviate cisplatin-induced chronic kidney injury by targeting the mTOR-dependent TFEB signaling pathway

An integrated proteomic and phosphoproteomic landscape of chronic kidney disease.

The prevalence of chronic kidney disease (CKD) is gradually rising worldwide. Patients often remain asymptomatic for an extended period, leaving them unaware of their condition, which can lead to progressing to end-stage renal disease and cause significant economic burden. Improved understanding of CKD pathogenesis can enhance early detection and facilitate advances in drug development. Here, we performed proteomic and phosphoproteomic analyses of the mouse unilateral ureteral obstruction model to explore the molecular mechanisms of chronic kidney injury. 474 significantly differentially expressed proteins and 96 significantly differentially expressed phosphoproteins were screened, respectively. Chronic kidney injury involves complex metabolic pathways such as citrate cycle and hematopoietic system in proteome, and mitochondrial oxidative phosphorylation suppression is a notable alteration. The phosphoproteomic analysis revealed a significant upregulation in epithelial mesenchymal transition and P53 pathways, with a corresponding increase in the phosphorylation of Jun at serine 73. Utilizing HK2 cells, we observed that the reduction oxidative phosphorylation was consistently associated with an augmentation in oxidative stress, which subsequently activated Jun and induced apoptosis. Proteins that act as hubs in these pathways may be candidate targets for CKD intervention. These findings contribute significantly to the current understanding of CKD and provide valuable insights for future studies. SIGNIFICANCE: Chronic kidney disease (CKD) incidence rising annually with varied etiologies, kidney often irreversibly fibrotic, the treatment options are limited and often ineffective due to deficient understanding of renal fibrosis mechanisms. Despite the extensive efforts and numerous omics studies conducted on renal fibrosis, to date, no study has been undertaken to investigate the role of phosphorylated proteins in UUO models. Previously, we performed a comprehensive transcriptome and proteome analysis based on the CKD model, but the potential alterations in the phosphoproteome were not addressed. Here, an integrated proteomic and phosphoproteomic landscape of CKD was completed, which was the the first phosphoproteomic profiles of UUO model. Phosphoproteomic profile suggests that the epithelial mesenchymal transition and P53 pathways is significantly activated in mouse models of kidney injury, and the core protein Jun played a key role in CKD. And a preliminary correlation between P-Jun and oxidative phosphorylation was found base on HK2 cells. Our work contributes to a deeper understanding of the disease characteristics and molecular mechanisms of CKD. Identifying potential CKD targets from proteome and phosphoproteome may provide valuable insights for early diagnosis and treatment of CKD.

The Ku protein family regulates hyperglycemia-induced vascular endothelial cell inflammation by modulating P300 levels.

Endothelial inflammation caused by hyperglycemia contributes to cardiovascular complications in patients with diabetes. Diabetic kidney injury (DKI) is one of the most significant manifestations of diabetes-related renal damage, encompassing both acute and early chronic kidney injury. DKI involves pathological mechanisms linked to inflammatory responses and early renal damage, which, if left unchecked, may progress to diabetic kidney disease. Previous research indicates that both P300 and Ese-1 play pivotal roles in hyperglycemia-induced endothelial inflammation. This study suggests that P300 modulates Ese-1 expression, promoting hyperglycemia-mediated vascular endothelial inflammation and thereby contributing to the occurrence and progression of DKI. Our findings revealed increased levels of tumor necrosis factor α (Tnf-α), p65 phosphorylation, and monocyte chemotactic proteins Mip-1β and Mip-2 in the kidney tissues of diabetic mice and hyperglycemic human renal glomerular microvascular endothelial cells (HRGECs). Additionally, hyperglycemia orchestrated endothelial inflammation through the upregulation of Ese-1 expression in vitro. Furthermore, P300 was found to be upregulated both in vitro and in vivo. Moreover, silencing P300 reduced hyperglycemia-induced inflammatory effects, which could be reversed by overexpressing Ese-1 in HRGECs. Further, P300 was observed to interact with the Ku protein family (Ku70/Ku86), which were downregulated in the kidney tissues of diabetic mice and hyperglycemic HRGECs. siKu70 and siKu86 intensified hyperglycemia-induced endothelial inflammation, an effect counteracted by P300 silencing. In essence, the Ku protein family interacts with P300 to modulate Ese-1 expression in HRGECs, thereby participating in hyperglycemia-induced endothelial inflammation.

RISK FACTORS OF CHRONIC KIDNEY INJURY AMONG DIABETIC AND NON-DIABETIC HEMODIALYSIS PATIENTS IN DUHOK GOVERNORATE, KURDISTAN REGION OF IRAQ

ABSTRACT Background: The number of patients with chronic kidney disease and those requiring dialysis is increasing markedly and can be considered as a major public health challenges. The current study aims to report on the risk factors of chronic kidney injury among diabetic and non-diabetic hemodialysis patients in Duhok Governorate, Kurdistan Region of Iraq. Methods: This is a cross-sectional study conducted in facilities that provide dialysis treatment in Duhok province, Kurdistan Region of Iraq. A total of 171 registered cases who diagnosed as a chronic renal failure requiring maintenance hemodialysis treatment were included. Results: The most common age group having chronic kidney injury was 55-69 years old. The results showed that most common factors were DM and hypertension. High creatinine level group were those aged 40-69 years and patients without DM show higher frequency of high S. Creatinine level. S. Creatinine was higher among non-controlled diabetic patients. Conclusions: Proper evaluation and screening of risk factors, and appropriate intervention and treatment of underlying causes, and regular follow up is needed to reduce the overall cost and economic burden and to minimize the consequences and improve the prognosis of patients with chronic kidney injury especially those with diabetes mellitus and hypertension.

Total Anti-oxidant Capacity and Immunosuppressive Drug Blood Levels after Kidney Transplantation: A Patent Perspective

Background: It is well known that acute or chronic kidney injury could be due to free radicals and pro-oxidants. This investigation aimed to monitor tacrolimus or cyclosporine blood trough levels and anti-oxidant capacity after kidney transplantation. Methods: There was no intervention in the routine management of transplant recipients. The sample size (n=70) included healthy individuals and kidney-transplanted recipients (n=25 on tacrolimus and n=10 on cyclosporine). The study population was matched for age. The attained information was examined by using the Statistical Package (SPSS Inc, Chicago, IL, USA). The significance level was considered as P ≤ 0.05. Results: In healthy individuals, the mean ± SD for the capacity of antioxidants was 91.9 ± 16.6 (u/ml), which was significantly higher when compared to the mean value of 28.5 ± 22.6 (u/ml) versus 24.7 ± 25.5 (u/ml), kidney recipients with tacrolimus versus cyclosporine (P ≤ 0.04) as immunosuppressive drugs. The mean value of tacrolimus levels was 14.6 ± 6.4 (ng/ml). The correlation between tacrolimus and cyclosporine trough levels and anti-oxidant capacity was 0.19 (P ≤ 0.14). There were no significant differences regarding age in cases and controls (P ≤ 42). Conclusion: This study showed that the capacity of anti-oxidants in kidney transplant recipients, those on tacrolimus or cyclosporine, might be lower than in healthy individuals. Subsequent investigations are recommended to delve into the therapeutic consequences of the influence of antioxidant therapies on the clinical outcomes of transplanted recipients. conclusion: Worldwide, our study is the first that showed that TAOC in kidney transplanted recipient was lower than controls

Trimethylamine Induced Chronic Kidney Injury by Activating the ZBP1-NLRP3 Inflammasome Pathway.

Trimethylamine N-oxide (TMAO), a bioactive metabolite of gut microbes, plays a pivotal role in the pathogenesis of kidney diseases by activating programmed cell death (PCD) pathways. However, whether trimethylamine (TMA) contributes to chronic kidney injury and which kind of PCD is involved in TMA-induced chronic kidney injury has not been previously evaluated. To observe the effect of TMA, male C57BL/6J mice were randomly divided into two groups: the Control group and the TMA group. The mice in the TMA group were intraperitoneally injected with 100 micromol/kg/day TMA for three months, whereas the mice in the Control group were injected with normal saline for the same period. After three months, plasma creatinine and blood urea nitrogen levels, indicators of kidney function, increased significantly in the TMA group as compared with those in the Control group. Furthermore, Masson staining assay showed that TMA treatment led to a larger area of fibrosis than the Control group. TMA treatment did not change the Bax/Bcl-2 ratio, RIP1, RIP3 and MLKL phosphorylation, or iron and malondialdehyde levels in kidney tissues, indicating that apoptosis, ferroptosis and necroptosis were not involved in TMA-induced chronic kidney injury. However, compared with the Control group, TMA treatment significantly upregulated NLRP3, Caspase-1, IL-1beta, cleaved-Caspase 8, Caspase-8, and ZBP1 protein expression in kidney tissues. These results indicated that the ZBP1-NLRP3 inflammasome pathway was involved in TMA-induced chronic kidney injury. In conclusion, our studies revealed that the ZBP1-NLRP3 inflammasome may take part in the progression of TMA induced chronic kidney injury.

The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis

Endoplasmic reticulum (ER) stress is a condition in which the ER is overwhelmed and unable to manage its protein load properly. The precise activation mechanisms and role of ER stress in kidney disease remain unclear. To study this, we performed unbiased transcriptomics analysis to demonstrate ER stress in kidneys of patients with chronic kidney disease and in mouse models of acute and chronic kidney injury (cisplatin and unilateral ureteral obstruction and reanalyzed previously published data on folic acid and mitochondrial transcription factor A(TFAM) knockout mice). Inhibiting the protein kinase RNA-like ER kinase (PERK) arm of ER stress but not activating transcription factor 6 or inositol-requiring enzyme 1, protected mice from kidney fibrosis. The stimulator of interferon genes (STING) was identified as an important upstream activator of ER stress in kidney tubule cells. STING and PERK were found to physically interact, and STING agonists induced PERK activation in kidney tubule cells. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. We also generated mice with a tubule specific STING deletion that were resistant to ER stress and kidney fibrosis. Human kidney spatial transcriptomics highlighted a spatial correlation between STING, ER stress and fibrotic gene expression. Thus, our results indicate that STING is an important upstream regulator of PERK and ER stress in tubule cells during kidney fibrosis development.

Proteinuria and proximal tubular epithelial cells: correlation between immunofluorescence, histology, and degree of proteinuria.

Proteins are filtered from the blood through the glomerular filtration barrier. Filtered proteins are reabsorbed by proximal tubular epithelial cells (PTECs), which have been shown to possess the ability to regulate protein reabsorption. Histologically, these reabsorbed proteins are seen as tubular protein reabsorption droplets (TPRDs). Experimental studies indicate that PTECs play an important role in regulating proteinuria but the correlations between TPRD and the degree of proteinuria in human kidney biopsies have not been investigated in detail. Consecutive native kidney biopsies with non-proliferative glomerular disease performed at the OSUWMC for a 1-year period were analyzed. Cases with acute glomerular diseases and inadequate biopsies were excluded. The staining intensity and the percentage of TPRDs, as well as other morphologic parameters, were assessed. A total of 109 kidney biopsies were included in the study. A reverse correlation was identified between the percentage of albumin TPRDs and proteinuria (p = 0.047). There were positive correlations between proteinuria and the staining intensity for IgG TPRDs (p = 0.05) and the degree of acute tubular necrosis (ATN) (p = 0.015). In patients with no ATN, positive correlations between proteinuria and albumin and IgG TPRDs were seen, whereas in patients with ATN, these correlations were lost. A positive correlation was seen between proteinuria and chronic kidney injury. A strong correlation was noted between the degree of proteinuria and podocyte foot process effacement. Our data indicate that PTECs regulate proteinuria by absorbing proteins from the urine filtrate. Therefore, based on the human renal biopsy material, our study confirms that well-functioning renal PTECs play an important role in the regulation of proteinuria.

Oxidative stress initiates hemodynamic change in CKD-induced heart disease.

Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12weeks of age while sham-operated swine served as controls. 5-6months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H2O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion.

Severe Combined Kidney Injury in an Hiv-Infected Patient Receiving Antiretroviral Therapy (Clinical Observation)

Kidney injury in patients infected with the human immunodeficiency virus (HIV) has a diverse spectrum. Some antiretroviral therapy (ART) drugs have nephrotoxic effects. We present a clinical case of severe combined kidney injury — chronic kidney disease (CKD) and acute kidney disease (AKD) — in a patient with HIV infection. She was on long-term treatment with a fixed-dose combination of rilpivirine, tenofovir, and emtricitabine and had normal pre-treatment renal function (estimated glomerular filtration rate 69 mL/min/1.73m2 ). There was gradual increase in blood creatinine, but the patient did not visit a nephrologist and the ART was not changed. The patient was admitted to the nephrology department two years later because she had arterial hypertension and hyperazotemia (blood creatinine 718 μmol/l). Diagnosis: chronic tubulointerstitial nephritis, CKD G5 taking into account the gradual increase in blood creatinine during long-term ART. The patient was treated with peritoneal dialysis. There was persistent decrease and stabilization of blood creatinine (210-190 μmol/l was) which indicated in AKD. The presented observation demonstrates that ART in an HIVinfected patient can lead to the development of severe combined chronic and acute kidney injury. HIV-infected patients receiving ART require regular monitoring of renal function and follow-up by a nephrologist.

Less Is More: Protective Effects of Caloric Restriction on Acute and Chronic Kidney Injury

Less Is More: Protective Effects of Caloric Restriction on Acute and Chronic Kidney Injury

Advances in AI-based combination therapies versus standard treatments for heart failure in patients with advanced kidney injury

Background: Recent advancements in AI and Machine Learning (ML) can help manage kidney disease and heart failure by providing predictive analytics and personalized treatment plans, improving diagnostic accuracy, and assisting clinicians in controlling chronic disease symptoms like acute kidney injury (AKI) and Managing Heart Failure (HF). We evaluated AI and ML role in predicting AKI and managing HF patients and it involved analyzing various predictive models and technologies to improve early detection provide personalized treatment, and enhance overall patient outcomes in complex renal and cardiac conditions. Methodology: We conducted our search on databases Scopus, PubMed, and Web of Science. Empirical evidence and state of the art of cutting-edge literature and real-time field research was analyzed. Results: AI advancements in HF management for advanced kidney disease AKI include unsupervised machine learning for risk stratification, reinforcement learning for predictive modeling and dynamic management, and LLMs and chatbots for diagnostic support and patient education. New developments in AI and medical technology are predictive analytics for AKI, automated ultrasound interpretation, AI-enhanced dialysis monitoring, HF risk prediction, remote monitoring, and telehealth integration, and making personal treatment strategies according to patient needs. Innovations like wearable dialysis devices, bioengineered kidney tissues, ECMO, LVADs, TAVR, SGLT2 inhibitors, CRT, and nephroprotective drugs have also improved patient outcomes as these have enabled personalized care and early intervention strategies. Conclusion: It is possible to conclude that AI has revolutionized AKI and HF management. Novel technologies offer precise and adaptive care that strictly addresses individual patient needs.

Sexually dimorphic renal expression of mouse Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b

Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice present normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.

A PDE1 inhibitor, vinpocetine, ameliorates epithelial-mesenchymal transition and renal fibrosis in adenine-induced chronic kidney injury in rats by targeting the DNMT1/Klotho/β-catenin/Snail 1 and MMP-7 pathways.

Tubulointerstitial fibrosis (TIF) is present with chronic kidney disease (CKD). Vinpocetine (Vinpo) is used for treating cerebrovascular deficits, exhibiting some kidney-beneficial effects; however, its role in TIF is uncertain. So, the aim of this study was to investigate its potential impact on adenine-induced fibrotic CKD and explore the underlying mechanistic aspects. Eighteen male Wistar rats were categorized into three groups (n = 6 each). Group I was kept as controls and given saline; group II received adenine (300 mg/kg, twice weekly, i.p.) for induction of the CKD model; and group III was administered Vinpo (20 mg/kg/d, orally) concurrently with adenine. All treatments were administered for 4 weeks. Vinpo revealed an improvement in renal function and an alleviation of inflammation triggered by adenine via diminishing serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels. Further, Vinpo repressed the epithelial-mesenchymal transition (EMT) with preserved E-cadherin mRNA expression and lowered gene and immune expression of fibronectin and vimentin, respectively, besides attenuating the elevated G2/M arrest-related molecules (renal Ki67 protein contents and p21 gene expression). Renal pathological alterations caused by adenine were attenuated upon Vinpo administration. Interestingly, Vinpo suppressed abnormal renal β-catenin immunoreactivity, Snail 1, and MMP-7 gene expression while simultaneously restored Klotho protein expression by downregulating DNA methyltransferase 1 enzyme (DNMT1) protein expression in the kidney. These data indicated that Vinpo effectively mitigated EMT and G2/M arrest-induced renal fibrosis in adenine-induced CKD rats by targeting DNMT1-associated Klotho suppression, subsequently inhibiting β-catenin and its fibrotic downstream genes.

Intracorporeal urinary diversion offers the advantage of delaying postoperative renal function injury in patients undergoing robot-assisted radical cystectomy.

To analyze changes in renal function and associated risk factors in patients with bladder cancer undergoing robot-assisted radical cystectomy (RARC) with intracorporeal or extracorporeal urinary diversion (ICUD or ECUD). Clinical-pathological data was extracted from electronic medical records of 266 patients with bladder cancer who underwent RARC at our institution between August 2015 and August 2022. Postoperative renal function was assessed using the estimated glomerular filtration rate (eGFR). Patients were classified into ECUD and ICUD groups based on the surgical approach. Significant differences in eGFR were observed between the two groups at 1, 2, and 3 years postoperatively. Moreover, 112 patients (42.1%) experienced long-term renal function injury. Independent risk factors for long-term renal function injury included the type of surgical approach, ureteroenteric anastomotic strictures, and pathological stage T3 or above. In terms of short-term renal function, 30 cases of acute kidney injury (AKI) were observed, with an incidence rate of 11.3%. No difference in AKI incidence was found between the groups. Postoperative AKI and chronic kidney injury are prevalent complications following RC. This study highlights that pathological stage, ureteroenteric anastomotic strictures, and ECUD significantly impact long-term renal function, but the type of urinary diversion (ileal conduit or orthotopic neobladder) had no effect on renal function, and ICUD was superior in terms of long-term renal injury rate. Therefore, precise preoperative assessment and the selection of appropriate surgical approach are crucial for preserving renal function in patients with bladder cancer.

Complex Assessment of the Functional State of the Urinary System in Preclinical Studies. Part 2. Markers of Nephrotoxicity (Review)

INTRODUCTION. The determination of nephrotoxicity markers is a useful and necessary step in the detection of renal injury in animal experiments; these markers help accurately localise organ damage. With multiple damaging agents, known nephrotoxicity mechanisms, and laboratory animal species, there is currently no widely accepted renal injury marker that meets all the prerequisites.AIM. This study aimed to collate literature data on nephrotoxicity markers, evaluate their prognostic significance, and formulate general recommendations for assessing urinary system function in preclinical studies.DISCUSSION. This article describes a comparative analysis of the nephrotoxicity markers recommended by regulatory authorities for monitoring drug-induced kidney injury. According to the results, the most commonly used and prognostically significant markers of acute kidney injury in preclinical studies are cystatin C, albumin, total protein, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin-2 (NGAL), and clusterin. Chronic kidney injury markers include the above, plus the glomerular filtration rate, creatinine, urea, and osteopontin. An electrolyte panel can be used for the differential diagnosis of pre-renal azotaemia and acute kidney injury. Potential limitations for the routine use of kidney injury markers in preclinical research include the high cost of their quantitative determination and the lack of information on the applicability of data obtained from different species of laboratory animals.CONCLUSIONS. Having compared the prognostic significance of common biomarkers, the authors provided general recommendations for a comprehensive preclinical assessment of urinary system function, including laboratory investigations, instrument-based tests, and necropsy. A preclinical study design should be based on the study aims, the species and number of animals used, and special considerations for the test article.

SGLT-2 inhibitors and nephrolithiasis risk: a meta-analysis.

Sodium-glucose cotransporter (SGLT)-2 inhibitors are novel anti-diabetic medications with potential beneficial effects on cardiovascular and renal outcomes, metabolic parameters, and body weight. In addition to the beneficial effects on renal functions, including estimated glomerular filtration rate and reduction in proteinuria, recent studies have investigated the potential role of SGLT-2 inhibitor therapy on nephrolithiasis development. Nephrolithiasis, a condition affecting almost 10% of the general population at least once during a lifetime, is a common disorder with considerable risk for acute and chronic kidney injury and relatively few effective therapeutic options. We have performed a literature search through multiple databases, including PubMed, Ovid/Medline, Web of Science, Scopus, and Cochrane Library. We have followed the systematic review and meta-analysis guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.We have included a total of 11635698 patients who experienced nephrolithiasis from six clinical trials to conduct this meta-analysis study. In the pooled analysis, nephrolithiasis occurred in 1,27% of patients from the SGLT2i group (n=739197), compared to 1,56% of patients (n=10896501) from the control arm (active control, placebo or no therapy). We have included a total of 11635698 participants who experienced nephrolithiasis from a total of six clinical studies with nephrolithiasis rates of 1,27% in the SGLT2i group (n=739197), compared to 1,56% in the control arm (n=10896501). SGLT-2 inhibitor therapy has been associated with a lower risk for nephrolithiasis compared to placebo (OR 0.61, 95% CI, 0.53-0.70, p<0.00001) or active therapy such as glucagon-like peptide 1 and dipeptidyl peptidase-IV inhibitors (OR 0.66, 95% CI, 0.47-0.93, p=0.02). We have demonstrated a lower risk of nephrolithiasis risk with SGLT-2 inhibitor therapy compared to placebo or active control. Potential underlying mechanisms include osmotic diuresis leading to a reduction in the concentration of lithogenic substances, anti-inflammatory and anti-fibrotic effects, and an increase in urine pH. There is a clear need for future large-scale randomized clinical trials evaluating such associations for better understanding.

Optimal timing of invasive intervention for high-risk non-ST-segment-elevation myocardial infarction patients.

To compare the immediate, early, and delayed percutaneous coronary intervention (PCI) strategies in non-ST-segment-elevation myocardial infarction (NSTEMI) patients with high-risk. Medical records of patients treated at the Daping Hospital, Third Military Medical University, Chongqing, China between 2011 and 2021 were retrospectively reviewed. Only patients with complete available information were included. All patients assigned into three groups based on the timing of PCI including immediate (< 2 h), early (2-24 h) and delayed (≥ 24 h) intervention. Multivariable Cox hazards regression and simpler nonlinear models were performed. A total of 657 patients were included in the study. The median follow-up length was 3.29 (interquartile range: 1.45-4.85) years. Early PCI strategy improved the major adverse cardiac event (MACE) outcome compared to the immediate or delayed PCI strategy. Early PCI, diabetes mellitus, and left main or/and left anterior descending or/and left circumflex stenosis or/and right coronary artery ≥ 99% were predictors for MACE outcome. The optimal timing range for PCI to reduce MACE risk is 3-14 h post-admission. For high-risk NSTEMI patients, early PCI reduced primary clinical outcomes compared to immediate or delayed PCI, and the optimal timing range was 3-14 h post-admission. Delayed PCI was superior for NSTEMI with chronic kidney injury. Delayed invasive strategy was helpful to reduce the incidence of MACE for high-risk NSTEMI with chronic kidney injury. An immediate PCI strategy might increase the rate of MACE.

Emodin inhibits M1 macrophage activation that related to acute and chronic kidney injury through EGFR/MAPK pathway.

Macrophages are the main inflammatory cells involved in kidney injury and play a significant role in the development of acute kidney injury (AKI) and progression of chronic kidney disease (CKD). Emodin is believed to stabilize macrophage homeostasis under pathological conditions. The objective of this study aimed to explore the underlying mechanisms and effects of Emodin on M1 macrophages. Network pharmacology methods were used to predict target proteins associated with renal injury and identify the pathways affected by emodin. RAW264.7 macrophages were induced into M1 polarization using LPS and then treated with emodin at 20, 40, and 80 µM. The effects of emodin on cell viability, cytokines (IL-1β, IL-6, TNF-α), M1 macrophage markers (F4/80 + CD86+), and the EGFR/MAPK pathway were evaluated. Additionally, we transfected RAW264.7 cells with an EGFR shRNA interference lentivirus to assess its effects on RAW264.7 cells function and MAPK pathway. After RAW264.7 cells were passaged to expanded culture and transfected with EGFR-interfering plasmid, macrophages were induced to polarize towards M1 with LPS and then treated with 80 µM emodin. CKD modeling was performed to test how emodin is regulated during CKD. There are 15 common targets between emodin and kidney injury, of which the EGFR/MAPK pathway is the pathway through which emodin affects macrophage function. Emodin significantly reduced the levels of IL-6, IL-1β and TNF-α (p < 0.05) and the ratio of M1 macrophage surface markers F4/80 + CD86+ (p < 0.01) in the supernatant of RAW264.7 cells in a dose-dependent manner. Furthermore, the inhibitory effect of emodin on RAW264.7 cells was achieved by interfering with the EGFR/MAPK pathway. Moreover, emodin also affected the mRNA and protein expression of EGFR and Ras, leading to a decrease in the rate of M1 macrophages, thus inhibiting the pro-inflammatory effect of M1 macrophages. The addition of emodin reduced the rate of M1 macrophages in CKD and inhibited the further polarization of M1 macrophages, thus maintaining the pro-inflammatory and anti-inflammatory homeostasis in CKD, and these effects were achieved by emodin through the control of the EGRF/ERK pathway. Emodin attenuates M1 macrophage polarization and pro-inflammatory responses via the EGFR/MAPK signalling pathway. And the addition of emodin maintains pro- and anti-inflammatory homeostasis, which is important for maintaining organ function and tissue repair.